PROJECT ABSTRACT Neurodegenerative disorders, including Alzheimer?s disease (AD) and related dementias (ADRD), affect over 47 million people worldwide, and this number is anticipated to reach 131.5 million by 2050.1 Because no medication successfully reverses the course of dementia, researchers are focusing increasing efforts on prevention by addressing potentially modifiable risk factors. Recent evidence suggests that air pollution, a ubiquitous environmental exposure, may be linked to neurodegeneration and dementia. This project aims to advance the state of the science on this topic through biologically-based epidemiological analyses. In the first aim of this project, I will evaluate the association between PM2.5 exposure and markers of damage and early disease, including AD-related pathologies (?-amyloid1-42 (A?1-42), tau, and phosphorylated tau), oxidative stress biomarkers (F2-isoprostanes (F2-IsoPs)), and cerebrovascular injury biomarkers (E- selectin, vascular cell adhesion molecule-1) in the cerebrospinal fluid (CSF) of cognitively normal and demented individuals. In the second aim, I will utilize autopsy specimens to evaluate the association between PM2.5 exposure and biomarkers of AD ((?-amyloid1-42 (A?1-42) and tau) in the temporal, frontal and parietal lobes of cognitively normal and demented individuals. In the third aim, I will evaluate the association between long term average, recent past, and earlier past PM2.5 exposure and incidence of dementia (AD and all-cause). This proposed work will advance scientific understanding of the mechanisms and risk factors for dementia, a clear strategic goal of the National Institute on Aging. Furthermore, the findings of this research could inform policies to reduce exposure to air pollution, which could decrease the burden of environmental-related dementia across the population.